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Genetics in Congenital Disorders of the

Gastrointestinal Tract

26th International Congress of Pediatrics, Tehran, Iran

M. Rafati MD PhD Assistant Professor of Medical

Genetics Avicenna Research Institute

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Gastrointestinal Disorders

Classification

Gross defects of the anatomical structures Atresia Abdominal wall defects Defects of the diaphragm Anorectal malformations Malrotation

Congenital intestinal aganglionosis Malfunction or malformation of hepatobiliary system Functional disorders

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Abdominal Wall Defects

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Gastroschisis and Omphalocele

Relatively common disorders among newborns: 1981: 1 to 2 per 10000 births (>500000 live births

investigated) 2014: 7.4 per 10000 births (3,806,299 live births

investigated)

Note: increasing prevalence during recent years

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Contribution of Genetics

Isolated or Associated with

Other Anomalies?

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Genetics in Gastroschisis and Omphalocele

Multifactorial disorder

Chromosome abnormalities

Mendelian inheritance Few reported families

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Study design

J Pediatr Surg. 2014 Apr;49(4):514-9.

The increasing prevalence of abdominal wall defects prompted analysis of anomalies associated with gastroschisis and omphalocele in the Texas Birth Defects Registry (TDBR).

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Results Analysis of 2825 cases including:

1831 of gastroschisis (64%) 814 of omphalocele (28.5%) 180 of unspecified abdominal wall defects

Plus 9680 associated anomalies that were classified according to system.

The overall prevalence of abdominal wall defects among 3,806,299 Texas births from 1999 to 2008 was:

7.4 per 10,000 4.8 per 10,000 for gastroschisis  2.1 for omphalocele

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Association with other anomalies

Gastroschisis: 594/1831 (32%) Omphalocele: 654/814 (80%)

Gastroschisis as well as omphalocele has significant associated anomalies that are important to appreciate during pre- and postnatal management.

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Recurrence Risk

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Am J Med Genet. 1993 Feb 15;45(4):465-7

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Results In a population-based study of gastroschisis that included an

extended pedigree of all probands, 6 (4.7%) out of 127 families had more than one affected relative.

The relationships of the affected were: sib, half-sib (2), first cousin, second cousin once removed, and great uncle.

Sib recurrence was 3.5%.

Our results suggest that pregnancies occurring in a family with a history of gastroschisis may be at higher risk of recurrence than previously thought.

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Study designBirth Defects Res A Clin Mol Teratol. 2011 Oct;91(10):873-8. 

Gastroschisis remains an epidemiologic and pathogenetic dilemma

The purpose of this study was to determine which gastroschisis cases in the Utah Birth Defect Network (UBDN) were related and the excess familial risk among multigenerational families.

Gastroschisis cases born from 1997 through 2008 were investigated

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Familial Cases Of the 284 UBDN gastroschisis cases, one in 40 (n = 7;

2.5%) were reported to have another affected family member.

Among these seven cases, Three had affected sib pairs Four reported either a distant cousin, paternal uncle, maternal

half-uncle, or paternal cousin with gastroschisis.

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Conclusion A statistically significant excess risk

for gastroschisis because of familial factors was found.

Similar to many other birth defects, gastroschisis may fit a multifactorial model of inheritance.

Genetic susceptibility should be further investigated because it may have a greater role in the etiology of gastroschisis than currently appreciated.

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Importance of Diagnosis

Pathology and genetic investigation of products of conception

Diagnosis

Genetic Investigation

Prevention in Future

Pregnancies

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Diagnostic approach

Chromosome study Karyotype Array-based techniques

Monogenic disorders Targeted molecular genetic study Genomic studies (next-generation sequencing

technique)

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Chromosome study

Normal karyotype does not rule out chromosome abnormalities

Array-based techniques Different resolution

CGH array Oligoarray SNP array

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Next generation sequencing techniques

High throughput Molecular investigation of a wide range of genetic

disorders in a single experiment Whole exome sequencing

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Thanks for Your Attention

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